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2. Session 3:
Drug Manufacture, Industrial Pharmacy
Considerations, Quality Assurance,
and Regulation
Tom Layloff, Management Sciences for
Health
2

3. Objectives
• Be familiar with drug manufacturing requirements and industry
regulations
• Describe Good Manufacturing Practices (GMP)
• Understand requirements for developing domestic manufacturing
capabilities
• Differentiate between brand vs generics and the conditions for
interchange
• Become familiar with the procedures to prevent and detect counterfeit
products
• Describe relevant drug regulations
• Describe the Guiding Principles for small national drug regulatory
authorities
• Understand basics of and issues relating to drug product quality
assurance
• Understand differences relating to full-scale manufacturing, small-scale
institutional/local production, and extemporaneous compounding 3

4. The Drug Universe
• Begins with the Active Pharmaceutical Ingredient (API)
• APIs are chemicals have been shown through clinical studies to have
desirable properties when used appropriately.
• APIs are extracts from natural products or chemically or biologically
synthesized.
• The Safety and Efficacy (S&E) of APIs are established almost universally
through the exquisite guidelines developed through the International
Conference on Harmonization of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH), www.ich.org.
• The ICH guidelines are adopted into the laws and regulations of the ICH
countries (European Union, Japan and United States) where essentially
100% of the drug research is conducted and which constitute over 85%
of the world drug market.
4

5. ICH Quality Topics Checklist
Q1: Stability Q1A(R): Stability Testing of
New Drugs and Products
(Revised)
Q1B: Photostability Testing Q1C: Stability Testing for New
Dosage Forms
Q1D: Bracketing and Matrixing
Designs for Stability Testing of
Drug Substances and Drug
Products
Q2: Analytical Validation Q2A: Text on Validation of
Analytical Procedures
Q2B: Methodology
Q3: Impurities Q3A(R): Impurities in New Drug
Substances (Revised)
Q3B(R): Impurities in New Drug
Products (Revised)
Q3C: Impurities: Residual
Solvents
Q4: Pharmacopoeias Q4: Pharmacopoeial
Harmonisation
Q5: Biotechnological Quality Q5A: Viral Safety Evaluation Q5B: Genetic Stability Q5C: Stability of Products
Q5D: Cell Substrates
Q6: Specifications Q6A: Chemical Substances
with its Decision Trees
Q6B: Biotechnological
Substances
Q7: GMP Q7A: GMP for Active Pharmaceutical Ingredients
5

6. More on APIs
• Chemically synthesized APIs (Fine Chemicals) are produced primarily in the
Chindia economic block, Korea and Italy (near Milan).
• Biotechnology derived APIs are almost all manufactured in the ICH regions
• The clinical studies—Phase III—define the therapeutic window—more drug
may be toxic and less may be ineffective.
• Summary: Clinical studies are used to define the safety and efficacy of a drug
product containing the API and the therapeutic window.
6

7. Drug Products
• Excipients used to formulate APIs into drug products are generally food
grade chemicals—Bulk Commodities. Excipients are used to make the
drug more convenient, palatable or effective
– 325 mg Tylenol Excipients--cellulose, corn starch, magnesium
stearate, sodium starch glycolate
• Some Common Dosage Forms: Capsules, Tablets, Chewable Tablets,
Granules, Creams, Gels, Ointments, Injections, Powder for Injection, Oral
Solutions, Suspensions, Syrups, Powder for Suspensions, Suppositories,
Inhalers, Powder for Inhalation
7

8. New and Generic DrugsNew and Generic Drugs
• Generic drugs are off-patent products
• New and Generic Drugs frequently are give proprietary trade names for
market leverage. Tylenol brand acetaminophen and Bayer brand aspirin
are good examples of trade name off patent products. In Namibia I
encountered at a pharmaceutical distributor 28 trade named amoxicillin
products.
• The names of the API are assigned in the International Non-proprietary
Names (INN) by WHO or in the United States Adopted Names (USAN)
established by the AMA, USP and APhA.
8

9. New Drug Development
9

10. Drug Regulation
• Commerce Issues
– When you purchase a 100 tablet bottle of 325 mg Aspirin do you get
100 tablets?
– Does each Aspirin tablet contain 325 mg of Aspirin?
– 325 mg is a pharmaceutical “term of art.”
• Each tablet contains 85-125% and on the average they contain
90-110%.
• Chemically 325 mg means 324.6-325.4 mg.
• Therapeutic Issues
– Do the tablets disintegrate and release the drug for absorption?
– Are there undesirable impurities present in the formulation?
10

11. Commerce Issues
• Initially defined in pharmacopoeias which were established by practitioners
to govern commerce in therapeutic “weeds and seeds.” The United States
Pharmacopeia was established in 1820 by practitioners to govern their
commerce.
• Pharmacopoeias contain monographs which define testing procedures and
limits for assessing product quality.
• There are approximately 30 national pharmacopoeias from Argentina to
Yugoslavia in addition to the African, European and International
Pharmacopoeias.
• Identity, assay, dosage uniformity, API release from matrix, sterility,
impurities, etc.
• Since the USP already was the basis for commerce in the US when the
1906 FDA legislation was enacted, it was cited for regulation and law
enforcement of quality standards.
• The 1906 FDA legislation was a commerce law. It prohibits interstate
commerce in misbranded and adulterated foods and drugs.
11

12. Cascara Sagrada is the dried bark of
Rhamnus purshiana De Candolle
(Fam. Rhamnaceae).
• Usually in flattened or transversely curved pieces, occasionally in quills of
variable length and from 1 to 5 mm in thickness. The outer surface is
brown, purplish brown, or brownish red, longitudinally ridged, with or
without grayish or whitish lichen patches, sometimes with numerous
lenticels and occasionally with moss attached. The inner surface is
longitudinally striate, light yellow, weak reddish brown, or moderate
yellowish brown. The fracture is short with projections of phloem fiber
bundles in the inner bark.
12

13. 13

14. US FDA Legal Tipping Points
• 1938 Safety legislation enacted following the elixir sulfanilamide fiasco.
Sulfanilamide was dissolved in ethylene glycol to prepare a toxic elixir.
Drug products introduced into commerce after 1938 had to be shown to
be safe. Products marketed prior to 1938 were grandfathered and the
onus was on FDA to demonstrate lack of safety for action. Relived again
by accident in Haiti with the acetaminophen elixir prepared with impure
glycerol.
• 1941 Nearly 300 deaths and injuries result from distribution of
sulfathiazole tablets tainted with phenobarbital. The incident prompts
FDA to revise manufacturing and quality controls drastically, the
beginning of what would later be called good manufacturing practices
(GMPs).
• 1962 Efficacy legislation enacted following the thalidomide disaster. Drug
products introduced into commerce after 1962 had to be shown to be
effective for intended use. Drug products in commerce before 1962 were
reviewed for efficacy. Panels of experts were established by the National
Academy of Sciences-National Research Council to conduct the Drug
Efficacy Study Implementation (DESI).
14

15. A Generic Drug Is
• A generic drug is a drug that is bioequivalent to an innovator drug with
respect to pharmacokinetic and pharmacodynamic properties.
• Generic drugs must contain the same active ingredient at the same
strength as the innovator brand, be bioequivalent, and are required to
meet the same pharmacopeial standards as applicable.
• Generic drugs are identical in dose, strength, route of administration,
safety, efficacy, and intended use.
15

16. Hatch-Waxman Amendments to
FFD&C Act
• 1984 Legislation enacted to require FDA to approve applications to market
generic versions of brand-name drugs after expiration of patents and
exclusivities without repeating the research done to prove them safe and
effective thereby avoiding expensive pre-clinical and clinical trials. Abbreviated
New Drug Applications (ANDA).
• 1992 Generic Drug Enforcement Act imposes debarment and other penalties
for illegal acts involving ANDA.
• Bolar Pharmaceutical Company, pleaded guilty in 1991 to charges that it
submitted false test results to win Federal approval for some generic drugs.
16

17. New vs. Generic Review ProcessesNew vs. Generic Review Processes
New Drug (ICH) Generic Drug
Requirements Requirements
1. Chemistry 1. Chemistry
2. Manufacturing 2. Manufacturing
3. Controls 3. Controls
4. Labeling 4. Labeling
5. Testing 5. Testing
6. Animal studies
7. Clinical studies 6. Bioequivalence
8. Bioavailability 17

18. 1990s Generic Drug Fall-Out
• Circa is a cleaned-up reincarnation of Bolar Pharmaceuticals, a generic
drug maker whose chairman went to jail after the company was caught
faking a test for the Food and Drug Administration. And Pharmaceutical
Resources is the renamed Par Pharmaceuticals; officers of Par were
convicted of bribing F.D.A. regulators.
• FDA Manager Charles Chang, admitted receiving about $15,000 worth of
gifts, including furniture, computer equipment and an expense-paid trip to
Hong Kong, to help speed applications for generic drugs through the
approval process.
• Vitarine officials admitted that the data showing equivalence actually
came from tests on the brand-named drug, not the generic.
18

19. Preparing an API for Patient Use
• To serve the patient’s needs the API must be provided in the right amount in
an appropriate vehicle.
• Compounding: Good Compounding Practices. In the US the practice of
medicine and pharmacy is governed by state boards.
• “Production”
• Manufacturing: Current Good Manufacturing Practices. In the US API and
drug product manufacturing are governed by the US FDA.
19

20. Compounding
Compounding involves the preparation, mixing, assembling, packaging,
and labeling of a drug or device in accordance with a licensed
practitioner's prescription under an initiative based on the
practitioner/patient/pharmacist/compounder relationship in the course of
professional practice. Compounding includes the following:
a. Preparation of drugs or devices in anticipation of prescription drug
orders based on routine, regularly observed prescribing patterns.
b. Reconstitution of commercial products that may require the addition
of two or more ingredients as a result of a licensed practitioner's
prescription drug order.
c. Manipulation of commercial products that may require the addition of
one or more ingredients as a result of a licensed practitioner's
prescription drug order.
d. Preparation of drugs or devices for the purposes of, or as an incident
to, research, teaching, or chemical analysis.
20

21. USP Compounding Practices
< USP > Abbreviated Title
795 Nonsterile Compounding
797 Sterile Compounding
1075 Good Compounding Practices
1150 Pharmaceutical Stability
1160 Compounding Calculations
1191 Dispensing Stability
21

22. Manufacturing
• Manufacturing involves the production, propagation, conversion, or
processing of a drug or device, either directly or indirectly, by extraction of
the drug from substances of natural origin or by means of chemical or
biological synthesis.
• Manufacturing also includes
1. any packaging or repackaging of the substance(s) or labeling or
relabeling of containers for the promotion and marketing of such drugs
or devices;
2. any preparation of a drug or device that is given or sold for resale by
pharmacies, practitioners, or other persons;
3. the distribution of inordinate amounts of compounded preparations or
the copying of commercially available drug products; and
4. the preparation of any quantity of a drug product without a licensed
prescriber/patient/licensed pharmacist/compounder relationship. 22

23. Drug Manufacturing
• Mechanized Formulation
• API and Excipients are Blended and Processed into Products.
• Generally in Drug Manufacturing no chemical reactions are
conducted.
23

24. A Manufacturing Process
24

25. Granulation and Milling
• Granulation end-point
• Flow characteristics, bulk density etc
• Homogeneity of granule
• Moisture content
• Particle size
25

26. Good Manufacturing Practices (GMP)
• GMPs are intended to assure the production of a uniform, consistent
product. The WHO and US have published the flagship guidance. The
manufacturing processes must be well-defined, documented and in
demonstrated control.
• The GMP start with the quarantine of all received goods which after
verification are released to production.
• The GMP end with the review of the finished product to assure that it
complies with the stated requirements.
• It is estimated that the cost of quality manufacture costs 25-35% of sales.
26

27. Part 211 – Selected CGMP For
Finished Pharmaceuticals
Subpart E - Control of Components and Drug
Product Containers and Closures
211.80 General requirements.
211.82 Receipt and storage of untested
components, drug product containers, and
closures.
211.84 Testing and approval or rejection of
components, drug product containers, and
closures.
211.86 Use of approved components, drug
product containers, and closures.
Subpart F - Production and Process Controls
211.100 Written procedures; deviations.
211.101 Charge-in of components.
211.103 Calculation of yield.
211.105 Equipment identification.
211.110 Sampling and testing of in-process
materials and drug products.
211.111 Time limitations on production.
211.113 Control of microbiological contamination.
211.115 Reprocessing.
Subpart A - General Provisions
Subpart B - Organization and Personnel
211.22 Responsibilities of quality control unit.
211.25 Personnel Qualifications.
211.28 Personnel responsibilities.
Subpart C - Buildings and Facilities
211.46 Ventilation, air filtration, air heating and
cooling.
211.58 Maintenance
Subpart D - Equipment
211.63 Equipment design, size, and location.
211.65 Equipment construction.
211.67 Equipment cleaning and maintenance.
211.68 Automatic, mechanical, and electronic
equipment.
211.72 Filters.
27

28. Selected 211 CGMP Continues
Subpart G - Packaging and Labeling Control
211.122 Materials examination and usage
criteria.
211.125 Labeling issuance.
211.130 Packaging and labeling operations.
211.134 Drug product inspection.
211.137 Expiration dating.
Subpart H - Holding and Distribution
211.142 Warehousing procedures.
211.150 Distribution procedures.
Subpart I - Laboratory Controls
211.165 Testing and release for distribution.
211.166 Stability testing.
211.173 Laboratory animals.
• Subpart J - Records and Reports
• 211.182 Equipment cleaning and use log.
• 211.184 Component, drug product container,
closure, and labeling records.
• 211.186 Master production and control
records.
• 211.194 Laboratory records.
• 211.198 Complaint files.
• Subpart K - Returned and Salvaged Drug
Products
28

29. In Country Pharmaceutical
Formulation Capacity
• Can GMP Formulation Plants Be Established in the Developing
Countries??
• Can You Build Quality Toyota Vehicles In The US??
• Of Course
Fourth-largest automaker in America
12 manufacturing plants in North America -- two additional
facilities in the future
In 2004 at its North American facilities produced
• > 1.44 million vehicles,
• > 1.27 million engines and
• nearly 390,000 automatic transmissions
• Ford Eliminating Up to 30,000 Jobs and 14 Factories
• Commercial viability is crucial for sustainability!!
29

30. Reasons for Poor Quality Pharmaceuticals
• Gaps in regulatory capacity: improper requirements and no capacity for
implementation of requirements
• Global standards for generics: WHO has a comprehensive set of
guidelines, but implementation varies
• Different quality requirements for export: very few countries effectively
control quality of pharmaceuticals for export; certificates for export are
issued more easily than are certificates for domestic markets
• Financial incentives: local manufacturers do not have sufficient incentives
to meet international standards
• No enforcement actions.
30

31. Incorrect
amount
17%
No active
ingredient
60%Other errors
7%
Incorrect
ingredient
16%
Percentage breakdown of data
on 325 cases of substandard
drugs—including antibiotics,
antimalarials, and antituberculosis
drugs—reported to WHO
database from around the world
Substandard Medicines in Developing
Countries
Rägo, L. 2002. Ensuring Access to Drug Products That Are of
Acceptable Quality. PowerPoint presentation, WHO/EDM
Technical Briefing, October 2, Geneva.
31

32. Substandard Medicines in Developing
Countries
0 10 20 30 40 50
Brazil
Cambodia
El Salvador
Ghana
India
Laos
Myanmar
Nigeria
Tanzania
Thailand
Vietnam Therapeutic groups
• Analgesics
• Antihypertensives
• Antimicrobials
• Antimalarials
Percentage of Samples Found to Be Substandard
Rägo, L. 2002. Ensuring Access to
Drug Products That Are of Acceptable
Quality. PowerPoint presentation,
WHO/EDM Technical Briefing,
October 2, Geneva.
32

33. Quality Assurance: Product Testing
Malaysia
• Government Pharmaceutical
Laboratory purchases in 1992
GMP certification and product
testing
Costa Rica
• Social Security Fund purchases
in 1977 vs. 1991
Product testing program
33

34. 34
Quality of Antimalarial Products:
Both Content & Dissolution Are Problems

35. Current Testing Methods
• Color reactions
• Spectrophotometry
• Thin-layer chromatography (TLC)
• Gas chromatography
• High-performance liquid chromatography (HPLC)
• Others
35

36. Testing Standards and Methods
• Public vs. private standards (i.e.,
pharmacopeia vs.
manufacturer/registration)
• Legal vs. credentialed methods (i.e.,
pharmacopeia vs.
AOAC International)
36

37. Pharmacopoeial Assessments
• Rooted in the analytical methods developed in the drug discovery process –
technology dependent
• Discovery technologies are very focused on API and impurity
characterization (high-resolution systems)
• Relatively expensive systems:
Analytical equipment
Maintenance and other consumables
Reference materials
Personnel training
37

38. Implications for Resource-Limited
Settings
• Being largely import-dependent, developing countries need to develop and
maintain an effective product testing program. Two major hurdles are:
1. Newer essential therapeutic drugs for which public
standards/monographs are not available
2. Multisource essential therapeutic drug products for which the legal
reference methods require high- technology support
• Difficult to implement and sustain effective high-technology testing
programs:
1. Complexity of equipment and maintenance needs
2. Access to reference materials, reagents, and other consumables
3. Need for highly trained technical staff
4. Cost to launch and maintain effective program
38

39. Product Testing: Simple Methods
39

40. 40
Source: World Health Organization

41. Global Problem
How Do Producers Counterfeit?
1. Specially manufactured counterfeits
Sophisticated production facilities
• Excellent labeling
• All processes in-control
Generally no active ingredient
2. Hacker manufactured counterfeits
Poor quality products
• Non-uniform Colors
• Poor labeling
• Poor compression – powder, capping
Generally no active ingredient
41

42. Detection of Counterfeit Medicines
• A perfect counterfeit product cannot be detected.
• A well-made and well-labeled counterfeit is very difficult to detect even if
direct comparisons between authentic and fake products can be made.
• Testing may be the best available option.
42

43. • Counterfeit Detection by TLC--
Wrong Drug
• Metronidazole
Channel 1 = 100%
Channel 4 = 80%
• Quinine
Channels 2 & 3
43

44. Expired Chloroquine Injection Relabeled
Quinine Dihydrochloride Injection
Photo courtesy of Thomas Layloff 44

45. Quality Assurance: Monitoring
• Product problem reporting
Suppliers
Health care providers
Consumers
• Supplier and product database
Supplier performance
Product problems
• Clinical (ineffective, adverse events)
• Pharmaceutical (physicochemical problems)
45

46. Quality Assurance:
Evaluation and Enforcement
• Withdrawal of marketing authorization (product license)
• Delisting from prequalified status
• Rejection of shipment
• Product recall
46

47. Summary
• Many resource-poor countries are planning to purchase generics for ATM
and other diseases, so product quality is becoming a growing concern
• There are a number of program implications if substandard or counterfeit
products are purchased – poor treatment outcomes, potential liabilities, loss
of public trust
• More open (international) procurement can be financially beneficial, but
requires a more stringent QA system
• A three-tier testing program is a less expensive, viable option for quality
control – big laboratories are not always necessary
47